In non-small-cell lung cancer (NSCLC), sensitivity to tyrosine kinase inhibitors (TKIs) is associated with activating mutations and genomic gain of the epidermal growth factor receptor (EGFR). Preclinical data suggested that HER3 overexpression increases sensitivity to TKIs. A total of 82 NSCLC patients treated with gefitinib (250 mg), and previously evaluated for EGFR and HER2 status by fluorescence in situ hybridisation (FISH) and DNA sequencing, and for Phospho-Akt status by immunohistochemistry, were investigated for HER3 genomic gain by FISH. Patients with high polysomy and gene amplification were considered as HER3 FISH positive (+). HER3 FISH + pattern was significantly associated with female gender (P = 0.02) and never smoking history (P = 0.02). Patients with HER3+ tumours (26.8%) had a significantly longer time to progression (3.7 vs 2.7, P = 0.04) than patients with HER3-tumours, but not a significantly better response rate or survival. Patients with EGFR+/HER3+ tumours had higher objective response rate (36.4 vs 9.9%, P = 0.03) and time to progression (7.7 vs 2.7 months, P = 0.03) than patients with EGFR- and/or HER3- tumours, but no significantly longer survival. No difference in response was observed according to HER3 status in patients with EGFR+ tumours. Patients with HER2+/HER3+ tumours had similar outcome as patients with HER2- and/or HER3-tumours. Significantly different clinical end points were not observed between patients with HER3+/P-Akt+ and HER3- and/or P-Akt- tumours. Genomic gain for HER3 is not a marker for response or resistance to TKI therapy in advanced NSCLC patients.
Bibliographical noteFunding Information:
We are indebted to the Department of Pathology of the Bellaria Hospital-Bologna, Institute San Raffaele-Milano and Policlinico Monteluce-Perugia for providing patient tissues and clinical data, to AstraZeneca for providing the drug for treatment, and to the Cytogenetics and Tissue Procurement Cores of the University of Colorado Cancer Center for technical assistance. NCI grants Cancer Center Core Grant 2P30-CA46934, Specialised Program of Research Excellence P01-CA58187. FC was a Visiting Professor at the University of Colorado Health Sciences Center sponsored in part by the Department of Medical Oncology of the Bellaria Hospital, Bologna, Italy and in part by the Associazione Italiana Ricerca sul Cancro (AIRC) grant number 2881.
- Non-small-cell lung cancer
- Tyrosine kinase inhibitor